Particle design using supercritical fluids: Literature and patent survey

As particle design is presently a major development of supercritical fluids applications, mainly in the pharmaceutical, nutraceutical, cosmetic and specialty chemistry industries, number of publications are issued and numerous patents filed every year. This document presents a survey (that cannot pretend to be exhaustive!) of published knowledge classified according to the different concepts currently used to manufacture particles, microspheres or microcapsules, liposomes or other dispersed materials (like microfibers):RESS: This acronym refers to ‘Rapid Expansion of Supercritical Solutions’; this process consists in solvating the product in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapid nucleation of the product into a highly dispersed material. Known for long, this process is attractive due to the absence of organic solvent use; unfortunately, its application is restricted to products that present a reasonable solubility in supercritical carbon dioxide (low polarity compounds).GAS or SAS: These acronyms refer to ‘Gas (or Supercritical fluid) Anti-Solvent’, one specific implementation being SEDS (‘Solution Enhanced Dispersion by Supercritical Fluids’); this general concept consists in decreasing the solvent power of a polar liquid solvent in which the substrate is dissolved, by saturating it with carbon dioxide in supercritical conditions, causing the substrate precipitation or recrystallization. According to the solid morphology that is wished, various ways of implementation are available:GAS or SAS recrystallization: This process is mostly used for recrystallization of solid dissolved in a solvent with the aim of obtaining either small size particles or large crystals, depending on the growth rate controlled by the anti-solvent pressure variation rate;ASES: This name is rather used when micro- or nano-particles are expected; the process consists in pulverizing a solution of the substrate(s) in an organic solvent into a vessel swept by a supercritical fluid;SEDS: A specific implementation of ASES consists in co-pulverizing the substrate(s) solution and a stream of supercritical carbon dioxide through appropriate nozzles.PGSS: This acronym refers to ‘Particles from Gas-Saturated Solutions (or Suspensions)’: This process consists in dissolving a supercritical fluid into a liquid substrate, or a solution of the substrate(s) in a solvent, or a suspension of the substrate(s) in a solvent followed by a rapid depressurization of this mixture through a nozzle causing the formation of solid particles or liquid droplets according to the system.The use of supercritical fluids as chemical reaction media for material synthesis. Two processes are described: thermal decomposition in supercritical fluids and hydrothermal synthesis.We will successively detail the literature and patents for these four main process concepts, and related applications that have been claimed. Moreover, as we believe it is important to take into account the user's point-of-view, we will also present this survey in classifying the documents according three product objectives: particles (micro- or nano-) of a single component, microspheres and microcapsules of mixtures of active and carrier (or excipient) components, and particle coating.     

Micronization of fenofibrate by rapid expansion of supercritical solution

Micronization of fenofibrate was investigated using rapid expansion of supercritical solution (RESS) process. Effects of pressure, temperature and nozzle on particle size were optimized using Taguchi's orthogonal array and analyzed using XRD, DSC, FT-IR, SEM, laser diffractometer and dissolution testing. Processed fenofibrate retained crystalline structure and has a similar chemical structure with unprocessed fenofibrate. The average particle size of fenofibrate was reduced from its original 68.779 ± 0.146 μm to 3.044 ± 0.056 μm under the optimum condition (T at 35 °C, P at 200 bar and nozzle diameter at 200 μm). The processed fenofibrate showed an enhanced dissolution rate by 8.13 times.     

Generality of anomalous expansion of polymer chains in supercritical fluids

By using in-situ neutron reflectivity, we have investigated swelling isotherms of solvophilic and solvophobic end-grafted/non-grafted polymer chains on solid substrates in supercritical carbon dioxide and supercritical ethane. It was found that anomalous expansion of the polymer chains associated with excess absorption of the fluid molecules occurs in the large compressible regions of both supercritical fluids (SCFs) regardless of the polymer-fluid interactions. In addition, we found that the excess expansion of the solvophobic polymer chains in both SCFs collapse onto one master curve under the same magnitude of density fluctuations in the fluids. A simple thermodynamic two-state model along with the experimental results proposes that polymer chains are expanded independently of the polymer-fluid interactions to further change solvent density fluctuations around the polymer chains, thereby lowering the free energy of the polymer/SCF systems.     

超临界流体在制膜过程中的应用

介绍了超临界流体诱导相分离过程制备有机膜的工艺流程、原理及特点,并与传统的沉浸凝胶相转化制膜方法进行了比较。同时介绍了超临界流体过程在有机膜的制备和改性方面的研究现状及其研究前景,并对其进一步的研究提出了一些建议。     

Formation of ultrafine aspirin particles through rapid expansion of supercritical solutions (RESS)

The performance of pharmaceuticals in biological systems can be enhanced by reducing the particle size of pharmaceuticals. Rapid expansion from supercritical solution (RESS) has provided a promising alternative to comminute contaminant-free particles of heat-sensitive materials such as drugs. In this work, aspirin has been successfully precipitated by the RESS technology. The performances of the RESS process under different operating conditions are evaluated through the analysis of the particle characteristics. Our results show that extraction pressure and extraction temperature can significantly affect the morphology and size of the precipitated particles whereas the nozzle diameter and pre-expansion temperature are not observed to apparently influence the RESS particles. The RESS process could produce ultrafine spherical particles (0.1-0.3 μm) of aspirin as reflected by SEM observations.     

Polymeric hydrogels and supercritical fluids: The mechanism of hydrogel foaming

A novel method, the hydrogel foaming, is used in this work for the production of porous, polymer-based materials by processing with supercritical carbon dioxide (CO₂). This method is applied to crystalline hydrophilic polymers that, practically, exhibit no phase transition (melting or glass transition) below thermal decomposition temperature and, due to their crystallinity, do not absorb CO₂. Such polymers are mainly natural (semi)-crystalline polymers (e.g. chitosan, cellulose, etc.) for which the classical polymer foaming method with supercritical carbon dioxide is not applicable. The hydrogel foaming process (similar to classical polymer foaming) is applied to gelatin, chitosan, and gelatin/chitosan blend hydrogels that are physically crosslinked and may also be chemically crosslinked with glutaraldehyde vapour. After the foaming process, water is removed from the gels by mild freeze-drying leading to porous materials. Pore size control can be achieved by controlling different process parameters. Gelatin exhibits solubility in water up to high concentrations and forms thermoreversible hydrogels, rendering it a suitable choice for the investigation of the process mechanism. The mechanism of hydrogel foaming is explored on the basis of X-ray diffraction, calorimetry, rheology, sorption, Raman spectroscopy measurements and theoretical calculations with the NRHB (Non Random Hydrogen Bonding) equation-of-state model. The sorption and Raman spectroscopy measurements suggest that, besides dissolution in water (of the hydrogel), extensive CO₂ sorption by the polymer also occurs. Based on these results, a critical discussion is made and a mechanism for the hydrogel foaming is proposed.     

Mixing effects on particle formation in supercritical fluids

The process termed solution enhanced dispersion by supercritical fluids (SEDS™) is investigated. In the process particles are created in the rapid antisolvent process using a twin-fluid nozzle to co-introduce the SCF antisolvent and solution. Results of experimental and numerical studies are presented for two regions of pressure: above the mixture critical pressure where a single-phase exists for all solvent–antisolvent compositions, and below the mixture critical pressure where the two-phase region is observed. In experimental studies paracetamol (in the single-phase system) and nicotinic acid (in the two-phase system) were precipitated from ethanol solution using supercritical CO₂ as an antisolvent. To interpret the phenomena affecting creation of the supersaturation and to predict suprsaturation distribution, balances of momentum (flow), species (mixing), energy (heating and cooling) and population (droplet and crystal size distributions) are applied. The Favre averaged k–? model of the CFD code FLUENT is applied together with specific models for precipitation subprocesses and Peng–Robinson equation of state. This includes application of the PDF closure procedure for precipitation and the drop breakage kernel that is based on multifractal theory of turbulence for modelling drop dispersion. Thermodynamic effects of mixing and decompression are included as well. Predicted values not always agree with experimental data but anyhow simulations predict all trends observed in experiments.     

Synthesis of cerium oxide-based nanostructures in near- and supercritical fluids

Cerium-oxide based nanostructures attract increasing interest for their use in multiple applications. In particular, the substitution of Ce atoms by other elements with lower oxidation state is used to control oxygen vacancies within the oxide structures, which can greatly enhance the material properties for catalysis applications. Among the synthesis approaches, supercritical water (scH₂O) has been proved to be an extremely efficient media for the fast and facile elaboration of pure CeO₂ nanostructures, although substitution was little investigated with this method (precursors’ reactivity, mechanisms, etc.). Here, the influence of two cerium precursors – Ce(NO₃)₃·6H₂O and Ce(NO₃)₆(NH₄)₂ – in scH₂O synthesis was first investigated over the CeO₂ nanostructures synthesis process. Cerium ammonium nitrate was later used as precursor for the synthesis of Ce_1−x−yA_xB_yO_2−δ (A, B = Zr, Pr and/or La; 0 ≤ x, y ≤ 0.1). Supported by ICP analysis quantification, this study proposes an overview of the influences of residence time, temperature and precursors’ concentration over the proportion of the substitution element in the CeO₂ NCs. This work demonstrates a fast and simple process to Ce_1−x−yA_xB_yO_2−δ nanostructures synthesis using scH₂O synthesis.     

Particle formation in supercritical fluids—Scale-up problem

The process of antisolvent precipitation of particles, termed solution enhanced dispersion by supercritical fluids (SEDS™), is applied to precipitate the model drug, paracetamol, from ethanol solutions. In the SEDS process the substrate solution is quickly mixed in a mixing chamber of the coaxial two-component nozzle with an antisolvent, represented in this case by the supercritical CO₂. Resulting partially mixed, highly supersaturated solution is introduced into the precipitation vessel as a jet, which generates intensive circulation of residual fluids that dilute the fresh supersaturated solution. Nucleation starts in the nozzle chamber, whereas particle growth completes the process in the precipitation vessel. The process is carried out above the mixture critical pressure; the antisolvent is thus completely miscible with the solvent. Under such conditions the macro-, meso-, and micro-mixing processes can affect the particle size distribution (PSD) and should be considered when the process is scaled up. Scaling up considerations of the precipitation process are based on scale-up rules, CFD simulations and experimental data for paracetamol precipitation. In simulations the model presented earlier (Ba?dyga et al., 2004) that is based on the population balance equation and CFD modelling of compressible flow processes is applied. Results of experimental investigations and numerical simulations are applied to verify scale-up strategies for the SEDS processes.     

Particle generation for pharmaceutical applications using supercritical fluid technology

In the pharmaceutical industry, an even greater number of products are in the form of particulate solids. Their formation, formulation and the control of their user properties are still not well understood and mastered. Since the mid-1980s, a new method of powder generation has appeared involving crystallisation with supercritical fluids. Carbon dioxide is the most widely used solvent and its innocuity and “green” characteristics make it the best candidate for the pharmaceutical industry. Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti Solvent (SAS) and Particles from Gas Saturated Solutions (PGSS) are three families of processes which lead to the production of fine and monodisperse powders, including the possibility of controlling crystal polymorphism. For the RESS process, the sudden decompression of the fluid in which a solute has been dissolved is the driving force of nucleation. CO₂ is, however, a rather feeble solvent and this is obviously the main limitation of the development of RESS. In the SAS process, CO₂ acts as a non-solvent for inducing the crystallisation of a solute from an organic solution. The versatility of SAS (there is always a proper solvent-antisolvent couple for the studied solute) ensures future developments for very different types of materials. PGSS uses the fact that it is much easier to dissolve CO₂ in organic solutions (or melted compounds) than the contrary. It presents very promising perspectives of industrial development. After almost 20 years of active research, and more than 10 years of process development, this technology is reaching maturity, and very soon commercial drug produced by these techniques are likely to appear.     

Extraction and processing with supercritical fluids

OVERVIEW: Extraction and processing with supercritical fluids (SCF) is increasingly gaining importance in the food, pharmaceutical and chemical industries. Supercritical fluid extraction (SCFE) using carbon dioxide (CO₂) as a solvent has emerged as a highly popular technology today over the conventional techniques for extraction of natural products for rapid, contamination‐free, tailor‐made extracts having superior quality and shelf‐life and high potency of active ingredients. IMPACT: The importance of SCFE is on the rise due to consumers' preferences for ‘natural’ as opposed to synthetic substances and, impending regulations for environmental protection, safety, nutritive and toxicity levels. APPLICATIONS: Newer applications of SCFs include separation and purification of chemicals, cleaning, coating, particle formation, textile dyeing, aerogel drying, reactions with separation and food preservation. Some fundamental aspects of SCFs, various processing technologies with SCFs, and a few newer potential applications are presented in this article. Copyright © 2008 Society of Chemical Industry     

Particle size distribution by design

Particle size distribution (PSD) is often specified in product design and can have a significant impact on plant operations. To meet the target PSD, a four-step procedure is proposed. For the desired PSD, a functional structure that identifies the required changes to the particles is constructed. Then, specific equipment as well as recycle streams are identified. Finally, alternative processes are evaluated using discretized population equations to determine process feasibility and to select the best option. The procedure is illustrated with three examples—the production of salt, alumina, and metronidazole tablets.     

Preparation of anthracene fine particles by rapid expansion of a supercritical solution process utilizing supercritical CO<Subscript>2</Subscript>

The rapid expansion of a supercritical solution (RESS) process is an attractive technology for the production of small, uniform and solvent-free particles of low vapor pressure solutes. The RESS containing a nonvolatile solute leads to loss of solvent power by the fast expansion of the supercritical solution through an adequate nozzle, which can cause solute precipitation. A dynamic flow apparatus was used to perform RESS studies for the preparation of fine anthracene particles in pure carbon dioxide over a pressure range of 150–250 bar, an extraction temperature range of 50–70 °C, and a pre-expansion temperature range of 70–300 °C. To obtain fine particles, 100, 200 and 300 μm nozzles were used to disperse the solution inside of the crystallizer. Both average particle size and particle size distribution (PSD) were dependent on the extraction pressure and the pre-expansion temperature, whereas extractor temperature did not exert any significant effect. Smaller particles were produced with increasing extraction pressure and preexpansion temperature. In addition, the smaller the nozzle diameter, the smaller the particles and the narrower the PSD obtained.     

Investigation of the rapid expansion of supercritical solution parameters effects on size and morphology of cephalexin particles

The particle size of organic and inorganic materials is vital parameter to determine its final use. Most of the newly developed pharmaceutical materials are poorly soluble or insoluble in the aqueous media such as biological fluids. Particle size reduction of such pharmaceuticals is one of the clues to improve the dissolution rate, adsorption and bioavailability. In this study, the effect of extraction and expansion parameters of the RESS process such as extraction temperature (313–333 K), extraction pressure (140–230 bar), effective nozzle diameter (450–1700 μm), nozzle length (2–15 mm) and spraying distance (1–7 cm) on the size and morphology of the precipitated particles of cephalexin were investigated. The morphology and particle size of the unprocessed and processed (precipitated) particles were examined by the SEM images. The mean particle size of the precipitated particles was between 0.86 and 7.22 μm depending upon the different experimental conditions used. The precipitated cephalexin particles were close to spherical form while the unprocessed particles were irregular or needle in shape.     

Solubilities of solids in supercritical fluids

The solubilities of several low-volatility compounds in supercritical fluids were measured. The fluids used were pure carbon dioxide or carbon dioxide modified with small amounts of organic liquids. Some enthalpies of solution of solids in carbon dioxide at a density of 0.80 g/mL are presented. The enthalpy of solution of fluoranthene in carbon dioxide was found to be less endothermic at higher CO₂ density. The order of solubilities in the modified fluids was the same as that in the pure liquid modifiers. The same apparatus was used to measure vapor pressures of some substances as well as solubilities.     

Particle size analysis by transmission fluctuation spectrometry with band-pass filters

The transmission fluctuation spectrometry (TFS) is a recently-developed method for real-time, online/inline particle analysis in two-phase flows, whereby the particle size distribution (PSD) and particle concentration can be measured simultaneously. This study presents a new technique of data processing to the fluctuating transmission signal. Instead of low-pass filters, band-pass filters are employed to improve the resolution of the measurement on particle size distribution. Based on the layer model, an analytical expression of the spectrum of the fluctuating transmission through a monolayer is derived and hence the spectrum of the fluctuating transmission through a 3-dimensional suspension is formulated. The comparison between simulation and theory at low concentrations shows a satisfactory match. Measurements on a mono-modal suspension are presented. It is found that the measurements using band-pass filters are of better resolution in the PSD than those with low-pass filters.     

Homogeneously-catalyzed syntheses in supercritical fluids

Supercritical fluids (SCFs) differ from liquid solvents in a number of important properties, any of which could potentially alter the performance of a chemical reaction performed in a supercritical medium. Although rate, yield and selectivity improvements as well as environmental, health and engineering benefits are all possible, little research has been reported on homogeneously-catalyzed syntheses in SCFs. Several notable successes plus new techniques for solubilizing hydrophilic reagents in SCFs are encouraging further research in this growing field. This revised version was published online in June 2006 with corrections to the Cover Date.     

超临界流体在超细粉体制备中的应用

对超临界流体用于制备超细粉体的研究现状和主要研究成果进行了综述。介绍了近年来开发的一些新方法和新工艺 ,其中包括超临界溶液快速膨胀 (RESS)法 ,超临界流体脱溶 (SAS)法 ,超临界逆向结晶 (SRC)法 ,超临界干燥 (SD)法和超临界流体化学反应等。分析了这些新工艺新方法的原理、特点 ,技术上的可行性 ,应用前景 ,目前达到的水平与存在的问题 ,及今后发展需解决的关键问题等。